Ornaghi, F. | bioRxiv Science

bioRxiv2018

Neuregulin 1 type III reduces severity in a mouse model of Congenital Hypomyelinating Neuropathy

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 type III regulate Schwann cell fate and myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we rescued the myelination defects by early overexpression of neuregulin 1 type III. Surprisingly, the rescue was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 (Pmp2) and oligodendrocyte myelin glycoprotein (Omg). We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial neuregulin 1 type III signaling has beneficial effects and restores myelination defects during development in a model of CHN.\n\n\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@103281aorg.highwire.dtl.DTLVardef@3dc68eorg.highwire.dtl.DTLVardef@1b6c5feorg.highwire.dtl.DTLVardef@80e419org.highwire.dtl.DTLVardef@1ff2591_HPS_FORMAT_FIGEXP M_TBL C_TBL

neuroscience↗

bioRxiv2018

A nonsense mutation in Myelin Protein Zero causes congenital hypomyelination neuropathy through altered P0 membrane targeting and gain of abnormal function

Protein Zero (P0) is the major structural protein in peripheral myelin and mutations in the Myelin Protein Zero (Mpz) gene produce wide ranging hereditary neuropathy phenotypes. To gain insight in the mechanisms underlying a particularly severe form, congenital hypomyelination (CH), we targeted mouse Mpz to encode P0Q215X, a nonsense mutation associated with the disease, that we show escapes nonsense mediated decay and is expressed in CH patient nerves. The knock-in mice express low levels of the resulting truncated protein, producing a milder phenotype when compared to patients, allowing to dissect the subtle pathogenic mechanisms occurring in otherwise very compromised peripheral myelin. We find that P0Q215X does not elicit an unfolded protein response, which is a key mechanism for other pathogenic MPZ mutations, but is instead aberrantly trafficked to non-myelin plasma membranes and induces defects in radial sorting of axons by Schwann cells (SC). We show that the loss of the C-terminal YAML motif is responsible for P0 mislocalisation, as its addition is able to restore correct P0Q215X trafficking in vitro. Lastly, we show that P0Q215X acts through dose-dependent gain of abnormal function, as wildtype P0 is unable to rescue the hypomyelination phenotype. Collectively, these data indicate that alterations at the premyelinating stage, linked to altered targeting of P0, may be responsible for CH, and that different types of gain of abnormal function produce the diverse neuropathy phenotypes associated with MPZ, supporting future allele-specific therapeutic silencing strategies.

neuroscience↗